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Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has enabled better prognosis for patients with peritoneal surface malignancies. However, in older age groups, short -and long-term outcomes are still perceived as poor. We evaluated patients aged 70 and over and determine if age is a predictor of morbidity, mortality and overall survival (OS).

Cisplatin is commonly used during intraperitoneal chemotherapy however has well-established nephrotoxic side-effects. Sodium thiosulfate is often added to cisplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) protocols to mitigate this, however evidence regarding risk of hypernatraemia is scarce as of yet.

Abstract Background In mammals, males typically have shorter lives than females. This difference is thought to be due to behavioural traits which enhance competitive abilities, and hence male reproductive success, but impair survival. Furthermore, in many species males usually show higher parasite burden than females. Consequently, the intensity of selection for genetic factors which reduce susceptibility to pathogens may differ between sexes. High variability at the major histocompatibility complex (MHC) genes is believed to be advantageous for detecting and combating the range of infectious agents present in the environment. Increased heterozygosity at these immune genes is expected to be important for individual longevity. However, whether males in natural populations benefit more from MHC heterozygosity than females has rarely been investigated. We investigated this question in a long-term study of free-living Alpine chamois (Rupicapra rupicapra), a polygynous mountain ungulate. Results Here we show that male chamois survive significantly (P = 0.022) longer if heterozygous at the MHC class II DRB locus, whereas females do not. Improved survival of males was not a result of heterozygote advantage per se, as background heterozygosity (estimated across twelve microsatellite loci) did not change significantly with age. Furthermore, reproductively active males depleted their body fat reserves earlier than females leading to significantly impaired survival rates in this sex (P < 0.008). This sex-difference was even more pronounced in areas affected by scabies, a severe parasitosis, as reproductively active males were less likely to survive than females. However, we did not find evidence for a survival advantage associated with specific MHC alleles in areas affected by scabies. Conclusions Increased MHC class II DRB heterozygosity with age in males, suggests that MHC heterozygous males survive longer than homozygotes. Reproductively active males appear to be less likely to survive than females most likely because of the energetic challenge of the winter rut, accompanied by earlier depletion of their body fat stores, and a generally higher parasite burden. This scenario renders the MHC-mediated immune response more important for males than for females, which implies a relatively stronger selection pressure on MHC genes in males than in females.

Abstract Introduction Malignant peritoneal mesothelioma is a rare cancer with poor patient survival. Female gender has been identified as a positive prognostic factor. Recently, it has been suggested that the expression of estrogen receptor β in malignant mesothelioma leads to tumor suppression and a better prognosis. Case presentation We report the case of a 48-year-old Caucasian woman who is alive and disease-free seven years after the initial diagnosis and treatment of malignant peritoneal mesothelioma. Conclusion This patient's long survival may be attributable to a combination of factors, including minimal disease, complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy plus the estrogen receptor β positivity of the tumor.

Abstract Background We evaluate the long-term survival of patients with peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective peritoneal disease severity score (PSDSS) on outcomes. Methods One hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987-2006 were identified from a prospective institutional database. These patients either received no chemotherapy, 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy. Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinically relevant factors. Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test. Results Median survival was 5 months (95% CI, 3-7 months) for patients who had no chemotherapy, 11 months (95% CI, 6-9 months) for patients treated with 5 FU/LV, and 12 months (95% CI, 4-20 months) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy. Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy (p = 0.026). PSDSS staging was identified as an independent predictor for survival on multivariate analysis [RR 2.8 (95%CI 1.5-5.4); p < 0.001]. Conclusion A trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy. The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin.

Abstract Background Emerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF). It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1α) is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ) could be mediated through inhibition of tumoral HIF-1α. Method In vitro, the effects of ABZ on HIF-1α levels in human ovarian cancer cells (OVCAR-3) were investigated using hypoxic chamber or desferrioxamine (DFO) induced-hypoxia. In vivo, the effects of ABZ (150 mg/kg, i.p., single dose) on the tumor levels of HIF-1α and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR. Results In vitro, ABZ inhibited cellular HIF-1α protein accumulation resulting from placement of cells under hypoxic chamber or exposure to DFO. In vivo, tumors excised from vehicle treated mice showed high levels of both HIF-1α and VEGF. Whereas, tumoral HIF-1α and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGFmRNA (but not HIF-1αmRNA) was also found to be highly suppressed by ABZ. Conclusion These results demonstrate for the first time the effects of an acute dose of ABZ in profoundly suppressing both HIF-1α and VEGF within the tumor. This dual inhibition may provide additional value in inhibiting angiogenesis and be at least partially effective in inhibiting tumoral HIF-1α surge, tumor invasiveness and metastasis.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

BackgroundThe multi-institutional registry in this study evaluated the outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal metastases (PM) from small bowel adenocarcinoma (SBA).MethodsA multi-institutional data registry including 152 patients with PM from SBA was established. The primary end point was overall survival (OS) after CRS plus HIPEC.ResultsBetween 1989 and 2016, 152 patients from 21 institutions received a treatment of CRS plus HIPEC. The median follow-up period was 20 months (range 1-100 months). Of the 152 patients, 70 (46.1%) were women with a median age of 54 years. The median peritoneal cancer index (PCI) was 10 (mean 12; range 1-33). Completeness of cytoreduction (CCR) 0 or 1 was achieved for 134 patients (88.2%). After CRS and HIPEC, the median OS was 32 months (range 1-100 months), with survival rates of 83.2% at 1 year, 46.4% at 3 years, and 30.8% at 5 years. The median disease-free survival after CCR 0/1 was 14 months (range 1-100 months). The treatment-related mortality rate was 2%, and 29 patients (19.1%) experienced grades 3 or 4 operative complications. The period between detection of PM and CRS plus HIPEC was 6 months or less (P = 0.008), and multivariate analysis identified absence of lymph node metastasis (P = 0.037), well-differentiated tumor (P = 0.028), and PCI of 15 or lower (P = 0.003) as independently associated with improved OS.ConclusionThe combined treatment strategy of CRS plus HIPEC achieved prolonged survival for selected patients who had PM from SBA with acceptable morbidity and mortality.

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P

Mucus plugging of the respiratory tract occurs in airway diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. It can cause blockage of the airways, leading to breathlessness and lung failure. Here, we used a ventilatory setup to demonstrate the effect of BromAc® in dissolving mucus plugs in a novel ex vivo ovine obstructive lung model. Mucus simulant was filled into the trachea of freshly slaughtered ovine lungs and ventilated via an endotracheal tube (ETT) using Continuous Mandatory Ventilation. Predetermined single or repeated doses of Bromelain, Acetylcysteine (Ac), BromAc®, and saline control were administered via an Aerogen® vibrating nebulizer and ventilated for 30 or 60 min. Ventilatory recording of resistance, compliance, and tidal volume was conducted, and rheology pre- and post-treatment were measured. A significant decline in airway resistance (p < 0.0001) compared to the saline control was observed when treated with Bromelain, Ac, and BromAc®, with the latter showing a stronger mucolytic effect than single agents. The decline in resistance was also effective in shorter time points (p < 0.05) at lower doses of the drugs. Changes in compliance, peak pressure, and tidal volume were not observed after administration of the drugs. Rheology measurements revealed that BromAc®TM significantly reduced the viscosity of the mucin at the end of 30 min and 60 min time points (p < 0.001) compared to the saline control. BromAc® showed complete dissolution of the respiratory mucus simulant and improved ventilatory airflow parameters in the ex vivo ovine model. [ABSTRACT FROM AUTHOR]